2,3,7,8-Tetracblorodibenzo p-Dioxin (TCDD); Dioxin

CAS No.1746-01-6 

9th Report on Carcinogens

U.S. Department of Health and Human Services
Public Health Service
National Toxicology Program
rev. Jan01

First Listed in the Second Annual Report on Carcinogens as Reasonably Anticipated to be a Known Human Carcinogen updated to Known to be Human Carcinogen in the January 2001 addendum to the Ninth Report on Carcinogens. The revised profile listing TCDD as a Known to be Human Carcinogen was published as a result of ruling by the US Court of Appeals for the District of Columbia Circuit dismissing the request for an injunction to prevent the listing of TCDD as a "known human carcinogen" in the Ninth Report pending appeal of the district court's decision upholding the listing.

2,3,7,8-Tetrachlorodibenzo-p-dioxin (2,3,7,8-TODD or TCDD) is known to be a human carcinogen based on sufficient evidence of carcinogenicity from studies in humans, involving a combination of epidemiological and mechanistic information which indicate a causal relationship between exposure to TCDD and human cancer.

Subsequent to the 1981 listing of TCDD as "reasonably anticipated to be a human carcinogen" in the Second Edition of the Report on Carcinogens, there have been a number of reports of studies examining cancers in human populations exposed to TCDD occupationally or through industrial accidents. There has also been a concerted research effort examining the molecular and cellular events that occur in tissues of humans and animals exposed to TCDD.

Epidemiological studies of four high-exposure industrial cohorts in Germany, the Netherlands, and the United States reported an increase in overall cancer mortality (IARC V.69, 1997). Studies published through 1996 demonstrated statistically significant increases in relative risks for all cancers combined, lung cancer, and non-Hodgkin's lymphoma among highly exposed subcohorts. Increased risk for certain cancers was also reported in an updated examination of the, population exposed to TCDD during the 1976 industrial accident in Seveso, Italy. (Bertazzi et al., 1997).

The evidence that TCDD is a human carcinogen is also supported by experimental animal studies that have shown that TCDD induces benign and malignant neoplasms at multiple tissue sites in multiple species. In addition, a compelling body of evidence has been developed that indicates a basic similarity in the mechanism of induction of animal and human tissue biochemical and toxicological responses to TCDD. Since 1977, many independent animal studies of TCDD have all found TCDD to be carcinogenic. Tumors have been produced in rats, mice, and hamsters, in both sexes, in various strains, in multiple organs and tissues, and from multiple routes of dosing, including gastrointestinal (gastric instillation or dietary), dermal, and intraperitoneal. TCDD exposure leads to an increased frequency of cancers in a dose-dependent fashion. TCDD is also a potent promoter of cancer in liver and skin in two-stage initiation-promotion models for carcinogenesis. Increased incidences of cancers in laboratory animals following TCDD exposure include the following organs or systems; hepatobiliary, thyroid, lymphatic, respiratory, adrenal cortex, hard palate, nasal turbinates, tongue, and skin (Huff et al., 1994).

There is scientific consensus for a common mode of action of TCDD and other chlorinated dibenzodioxins, dibenzofurans, and planar PCBs. In humans and rodents, this involves events that stem from an initial binding of TCDD to the aryl or aromatic hydrocarbon (Ab) receptor. TCDD has the highest affinity of the chlorinated dioxins and furans for both rodent and human forms of the Ab receptor. The Ab receptor is a ubiquitous intracellular protein, found in cells of vertebrates including rodents and humans, which acts as a signal transducer and activator for gene transcription. Through activation of the Ab receptor, TCDD induces a wide spectrum of biological responses considered important to the carcinogenic process including changes in gene expression, altered metabolism, altered cell growth and differentiation, and disruption of steroidhormone and growth-factor signal transduction pathways. Similar Ab receptor-mediated responses have been observed in both humans and rodents at similar body burdens or tissue concentrations of TCDD (DeVito et al., 1995).. There is scientific consensus that binding to the Ab receptor is a necessary, but not sufficient, step in the elicitation of these TCDD-induced responses, including cancer.

One major difference between humans and rodents has been noted in relation to biological halflife; TCDD has a half-life of 5.8 to 11.3 years in humans compared with generally 10 to 30 days in rodents. Thus, TCDD accumulates in human tissue much more so than in most experimental animals following chronic low-dose exposure. This would suggest that responses to TCDD would be expected to occur in humans following prolonged exposures to lower daily doses than would be required to elicit similar responses in experimental animals.

There are equivocal findings of chromosomal aberrations in humans exposed in vivo to TCDD. In vivo and in vitro studies of human and animal cells have also given inconsistent findings of genetic toxicity of TCDD. TCDD is not believed to be mutagenic.

TCDD has a physical state of colorless to white needles. It is almost insoluble in water, slightly soluble in n-octanol, methanol, and lard oil, and soluble in organic solvents (dichlorobenzene, chlorobenzene, benzene, chloroform, acetone). TCDD is stable in water, DMSO, 95% ethanol, or acetone. It can undergo a slow photochemical and bacterial degradation but is normally extremely stable. TCDD, however, is degraded when heated in excess of 500 °C or when exposed to ultraviolet radiation under specific conditions. Photodecomposition does not occur in aqueous solution (HSDB, 1997; Lewis, 1996; Radian, 1991).

TCDD is an inadvertent contaminant in herbicide precursors and, thus, in the herbicides themselves (Schecter et al., 1997b; IARC V.69, 1997). Since TCDD is a byproduct of the manufacture of polychlorinated phenols, it has been detected in commercial samples of 2,4,5-trichlorophenol (2,4,5-TCP) and was found in the herbicide 2,4,5trichlorophenoxyacetic acid (2,4,5-T). Before 1965, commercial 2,4,5-T contained up to 30 ppm TCDD or more. By the mid-1980s, however, commercial 2,4,5-T contained no more than 0.01 ppm TCDD. Since 1971, regulatory agencies in a number of countries worldwide enforced a maximum of 0.1 ppm TCDD in 2,4,5-T. Agent Orange (a 50:50 mixture of the N-butyl esters of 2,4,5-T and 2,4-D that was used in the Vietnam War as a defoliant during 1962-1970) contained 2 to 30 ppm TCDD. It has also been detected in the herbicide 2-(2,4,5trichlorophenoxy)propionic acid (Silver), and may be present in o-chlorophenol, 1,2,4,5tetrachlorobenzene, Ronnel (fenchlorphos), and 2,4-D (OHMTADS, 1985).

USE

TCDD has no known commercial applications but is used as a research chemical.

TCDD is currently not produced commercially in the United States, but it is synthesized on a laboratory scale. It is not imported into the United States (OHEA, 1985).

Polychlorinated dibenzo-p-dioxins (PCDDs) (including TCDD) are also produced by paper and pulp bleaching (Silkworth and Brown, 1996); by incineration of municipal, toxic, and hospital wastes; PCB-filled electrical transformer fires; and smelters (Schecter, 1994). Because it is a byproduct of 2,4,5-TCP production, TCDD is also found as a contaminant in some phenoxy herbicides such as 2,4,5-T, in some pesticides such as chlorinated phenols, and in wood preservatives such as pentachlorophenol (Schecter, 1994; IARC V.69, 1997).

Chlorinated dibenzo-p-dioxins as well as their structural analogs and usual cocontaminants (the chlorinated dibenzofurans) are widespread environmental contaminants. They bioaccumulate throughout the food chain because of their lipophilic character and slow metabolism in vivo (De Jough et al., 1995). Food is the major source (>90%) of human exposure to chlorinated dibenzop-dioxins. An average daily adult intake of TCDD was estimated to be 47 pg/day. It has been estimated that the average intake of TCDD for an adult in the United States from meat alone was 23 pg/day, accounting for 50% of the total daily intake of TCDD from food sources. The average daily intakes of TCDD from milk, produce, and fish were 13 pg/day (27%), 5 pg/day (11 %), and 5 pg/day (10%), respectively of the total daily intakes in the United States. However, for certain subpopulations (recreational and subsistence fishers), fish consumption may be more important source of chlorinated dibenzo-p-dioxins. The maximum daily intake of TCDD for residents of the Great Lakes region who regularly consume fish from the Great Lakes was estimated to range from 390 to 8,400 pg/day. Breast-fed babies nursed by mothers residing near improperly controlled municipal incinerators or other sources of possible TCDD exposure are potentially exposed to TCDD in the milk.

EPA regulates TCDD under the Clean Water Act (CWA), the Federal Insecticide, Fungicide, and Rodenticide Act (FIFRA), the Resource Conservation and Recovery Act (RCRA), the Comprehensive Environmental Response, Compensation, and Liability Act (CERCLA), and the Toxic Substances Control Act (TSCA) as a hazardous waste and toxic pollutant. A reportable quantity of 1 lb (0.454 kg) has been established for TCDD. The maximum contaminant level for the chemical in community water systems and nontransient, non-community water systems is 3 x 10 mg/L. FDA regulates TCDD in beverages, specifically bottled water; the allowable concentration is also 3 x 10 mg/L. NIOSH has recommended that the exposure limit of TCDD be the lowest feasible concentration. OSHA regulates TCDD under the Hazard Communication Standard and as a hazardous chemical in laboratories. Regulations are summarized in Volume II, Table B-136.

ATSDR. Agency for Toxic Substances and Disease Registry. Toxicological Profile for Chlorinated Dibenzo-p-dioxins. Update (Final Report). Atlanta, GA: ATSDR, Public Health Service, U. S. Department of Health and Human Services. 1998. 678pp. NTIS Accession No. PB99-121998

Bertazzi, P.A., C. Zocchetti, S. Guercilena, D. Consonni, A. Tironi, M.T. Landi, and A.G. Pesatori. Dioxin Exposure and Cancer Risk. A 15-year Mortality Study After the "Seveso Accident." Epidemiology Vol. 8, No. 6, 1997, pp. 646-652.

DeVito, M.J., L.S. Birnbaum, W.H. Farland, and T.A. Gasiewicz. Comparisons of Estimated Human Body Burdens of Dioxin-Like Chemicals and TCDD Body Burdens in Experimentally Exposed Animals. Environ. Health Perspect. Vol. 103, 1995, pp. 820831.

Huff, J., G. Lucier, and A. Tritscher. Carcinogenicity of TCDD: Experimental, Mechanistic, and Epidemiologic Evidence. Annu. Rev. Pharmacol. Toxicol. Vol. 34, 1994, pp. 343-372.

IARC. International Agency for Research on Cancer. IARC Monographs on the Evaluation of the Carcinogenic Risks to Humans. Polychlorinated Dibenzo-para-dioxins and Polychlorinated Dibenzofurans. Vol. 69. 33 pp. Lyon, France: IARC, 1997.

Lewis, R.J. Sax's Dangerous properties of Industrial Materials. Ninth Edition. Vol. IV. Van Nostrand Reinhold. New York, NY, 1996

OHMTADS. Oil and Hazardous Materials Technical Assistance data System. Online database available from the Chemical Information System. 2,3,7,8 - Tetrachlorodibenzo-p-dioxin profile. Accession number 8300192, originally produced in 1982, 1985